Dihydropyridines structure

On the other hand, one of the intermediate structures, namely structure VII, seems to be possibly converted to 1,4- dihydropyridine structure (XI), from the structural point of view. Besides, since A max of band III14 for XI is expected to be similar to that of the above side peak,15 the appearance of this peak would indicate the actual formation of XI. From the observation that the appearance of this peak was always temporary, and also from the structural relation between XI and the end structure IX — the expected... 

One of the reaction intermediates seems to be swiftly and reversibly converted to 1,4- dihydropyridine structure via a side path branching off from the main path. 

Extensive structural modification was performed on the 4-(4-nitrophenyl)-1,4-dihydropyridine structure [52] which led to conpounds which can be conridered specific for the human Uj -AR, based on the reported resuhs (see for example conpounds 10-11 in Table 1). 

Mai A et al (2009) Study of 1, 4-dihydropyridine structural scaffold discovery of novel sirtuin activators and inhibitors. J Med Chem 52(17) 5496-5504... 

Figure 24 shows the voltammograms of these compound obtained at pH 10.0. NAD and NMN are reduced at about -0.9 and -1.0 V (Fig. 24, curves a and b), respectively however, nicotinamide was not reduced in the observed potential range (curve c). The ultraviolet spectrum of the NMN solution after controlled-potential electrolysis at -1.0 V showed the characteristic peak of 1,4-dihydropyridine structure at 340 nm, indicating that the nicotinamide moiety in NMN is also reduced on a gold electrode. From these results the order of reducibility can be given as follows NAD > NMN > nicotinamide. The fact that NMN (1) is more easily reduced than nicotinamide (2) is probably due to the presence of the pyridinium ionic form (Fig. 23). The relative reducibility of NAD will be discussed later.

Since the pyridine derivatives obtained as metabolic products of SKF 24260 are inactive (42), the importance of the dihydropyridine structure is clear. 

Calcium channel blockers (CCBs) prevent the flow of calcium ions through channels in heart tissue. Inhibiting calcium flow decreases the strength of contraction of the heart and decreases blood pressure. Most CCBs fall into the dihydropyridine structural class, with nifedipine (Adalat, A.132) being the prototypical example (Figure A.38). Nondihydropyridine CCBs include diltiazem (Cardizem, A.135) and verapamil (Calan, A.136). 

The dihydropyridine class of calcium channel blockers undergoes extensive first-pass oxidation by CYP3A isoforms to their pyridine metabolites, and several studies have shown that inducers and inhibitors of these P450s decrease and increase the blood concentrations of the active dihydropyridine structures, respectively (51). The calcium channel blockers verapamil and diltiazem are unrelated structures that also undergo significant metabolism by cytochromes... 

The substitution pattern of the 4-aromatic residue is also important for the activity, the ortho-substitution being the best one in terms of potency and selectivity. A Hansch analysis on a series of ortho-derivatives has shown a significant correlation between calcium antagonist activity and steric hindrance of the substituent, while no relationship was found for either electronic or lipophilic parameters [3]. The best SAR correlation was obtained when the B1 steric parameter (the Verloop parameter) was introduced into the analysis [4]. The calcium channel-blocking activity increases as B1 increases, which probably indicates that steric hindrance in the ortho-position is required to fix the dihydropyridine structure into a favorable conformation in which the aromatic group is approximately perpendicular to the dihydropyridine ring (Fig. 7.12). 

The normal mechanism for the transamination reaction is shown in Fig. 4.24 (R=H) and involves the condensation of alanine and pyridoxal phosphate to give an imine. A proton is lost from the imine to give a dihydropyridine intermediate. This reaction is catalysed by a basic amino acid provided by the enzyme as well as the electron withdrawing effects of the protonated pyridine ring. The dihydropyridine structure now formed is hydrolysed to give the products. 

The reaction of pyridine (V-acetylimines with phenylmagnesium bromide has been reported to give 2-phenyl-l,2-dihydropyridine derivatives as major products (Eq. 26).15 The structure of the 1,2-dihydropyridines is mainly based on a comparison of their UV spectra with those of l-hydroxy-2-phenyl-l,2-dihydropyridines. However, since the structures of the latter have recently been revised to 5-phenyl-2,4-pentadienyl oximes,180 further evidence for the 1,2-dihydropyridine structure would be desirable. 

Marazano [62] has proposed a metabolic scheme relating the production of the manzamines to the biosynthetic origin of sarain A [63] and halicyclamine A [64], These compounds share the dihydropyridinium salt and dihydropyridine structural motifs. 

De Matteis, E, C. Hollands, A.H. Gibbs, N. de Sa, and M. Rizzardini (1982). Inactivation of cytochrome P-450 and production of N-alkylated porphyrins caused in isolated hepatocytes by substituted dihydropyridines Structural requirements for loss of haem and alkylation of the pyrrole nitrogen atom. FEES Lett. 145, 87-92. 

Cleavage of a 1,2-diketone. Buchi and co-workers have published an interesting synthesis of the dimethyl ester of betalamic acid (2), a unit in the red and yellow pigments of plants of the order Centrospermae. The acid is a dihydropyridine derivative and is very sensitive to oxidation. Consequently a synthesis was devised in which the dihydropyridine structure was obtained only in the final step. This step was the oxidative cleavage of the nonenolizable diketone 1 with lead tetraacetate in benzene-methanol (1 1, 0°) to give the dimethyl ester of betalamic acid. 

The dihydropyridine structure will readily oxidize to hydroperoxide, which can then break down into ketonic and aromatic structures (Scheme XIX)-... 

Coleman and Petcavich (1978) [192] used FTIR to propose a route (Scheme XIX) via the initial formation of the Grassie ladder, followed by a tautomeric change to the polycyclic dihydropyridine structure. Oxidation followed, producing carbonyl groups, a prerequisite for the subsequent condensation reaction between adjacent ladder formations to give a final structure proposed by Potter and Scott and more fully reported by... 

FIGURE 8.6 Example of a preferred structure. In this case, the dihydropyridine scaffold. 

Fig. 1. Subunit structure of dihydropyridine-sensitive channels from skeletal muscle. Cartoon...

The effect of structural variation on crystal structure was studied for 12 phenyl-substituted derivatives of 6-amino-2-phenylsulfonylimino-l,2-dihydropyridine [37], The title compound contains both hydrogen bond donor and acceptor sites, and the... 

This section deals with the application of molecular orbital (MO) calculations in structure-activity relationship (SAR) analyses. Calcium channel-blocking 1,4-dihydropyridine (DHP) derivatives such as nifedipine (Fig. 9.10) are widely used in the therapy of cardiovascular disorders. 

After its isolation, the structure of alkaloid deplancheine (7) was unambiguously proved by several total syntheses. In one of the first approaches (14), 1,4-dihydropyridine derivative 161, obtained by sodium dithionite reduction of A-[2-(indol-3-yl)ethyl]pyridinium salt 160, was cyclized in acidic medium to yield quinolizidine derivative 162. Upon refluxing 162 with hydrochloric acid, hydrolysis and decarboxylation took place. In the final step of the synthesis, the conjugated iminium salt 163 was selectively reduced to racemic deplancheine. 

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